by Amy Allina and Cindy Pearson

The ad in Parade magazine showed a woman's back, naked except for a black lacy bra, with the headline "If you care about breast cancer, care more about being a 1.7 than a 36B," and text explaining that the 1.7 refers to the results of a test assessing a woman's risk of getting breast cancer.

The television ad presents a collage of images and voices of women of varying ages and races, speaking about why they believe that they are safe from breast cancer, followed by a voiceover explaining that no woman can be sure she is safe from the disease and all women are at risk for it.

The ads, which were created and paid for by the pharmaceutical company AstraZeneca, which sells the drug tamoxifen under the brand-name Nolvadex, seem to echo messages and sentiments long expressed by the women's health movement. Tamoxifen has been used for many years to treat breast cancer and was approved last year for use in reducing the risk of breast cancer.

But consumer health advocates fear the ads and AstraZeneca's marketing campaign will persuade women with no special risk for breast cancer to take tamoxifen Ñ a drug with very serious potential side effects. Public Citizen and the National Women's Health Network have filed a petition with the FDA calling on the agency to require stronger warnings on the drug label and the distribution of patient information guides outlining the risks of the drug. Dr. Susan Love, a noted breast cancer doctor and author of Dr. Susan Love's Breast Book, recently published a New York Times op-ed warning women that there are risks associated with tamoxifen.

For these and other public health advocates, the tamoxifen case shows the pharmaceutical industry's effort to coopt the breast cancer movement's demand for a prevention emphasis in confronting the disease. This cooptation, they believe, will put women's health at risk in two ways: through the likelihood of inappropriate and excessive prescription of dangerous drugs; and by the continued failure of the medical establishment to research and emphasize non-pharmaceutical approaches to prevention Ñ environmental toxins, diet, exercise and similar factors.

FROM TREATMENT TO "PREVENTION"

Tamoxifen has been in use for treatment of advanced breast cancer since 1977. It is a potent synthetic hormone that works by blocking the effects of estrogen in breast tissue so that it stops the growth of certain types of breast cancer tumors (those which grow by feeding on estrogen). Doctors prescribe tamoxifen as treatment to women who have had surgery to remove breast cancer in order to reduce the likelihood of a recurrence of the cancer. For women who have passed menopause, tamoxifen can reduce the risk of recurrence by 30 percent. More recently, it has also been used to prevent recurrence in premenopausal women.

Because it is less toxic than chemotherapy, tamoxifen offers significant benefits as a breast cancer treatment drug. But tamoxifen is not harmless. Common side effects include hot flashes, vaginal discharge or irritation, irregular menses and apparently depression. Tamoxifen use has also been shown to cause endometrial cancer, blood clots and eye damage.

In spite of these side effects and risks, for women with breast cancer who face a choice between chemotherapy and tamoxifen, tamoxifen may be an attractive option. When weighing it against the risk of a breast cancer recurrence and the side effects of chemotherapy, many women do not hesitate to accept the side effects and associated risks. There may also be some additional benefits to tamoxifen, such as preservation of bone density.

In the late 1980s and early 1990s, as the breast cancer movement emerged, activists began calling for a shift in priorities to place a greater emphasis on research to gain a better understanding of how and why the disease develops and how it can be stopped. With petition campaigns and other demonstrations of grassroots demand, activists demanded that the National Cancer Institute (NCI) find and provide more information about the causes of breast cancer and how women can prevent it.

One of the ways that researchers responded to this demand was by looking into whether tamoxifen could be used to prevent breast cancer in healthy women in addition to preventing recurrences in breast cancer survivors. Activists reacted with decided ambivalence to this new research direction. Some, such as Breast Cancer Action, a San Francisco-based group, opposed the research outright.

"When we talk about the need for breast cancer prevention, what we mean is that we need to address and eradicate the cause of breast cancer," explains Barbara Brenner, executive director of Breast Cancer Action. "Throwing pills at women does not address those causes, and the problem is compounded when the pills that they decide to research are ones that we know to have some very serious, even life-threatening, side effects."

But the economic realities of the U.S. medical research system worked against the kind of research that activists were urging and for a tamoxifen trial. The profit potential in a patentable pill to prevent breast cancer could draw industry interest, whereas research into the environmental causes of breast cancer or the prevention potential of a low-fat diet, for example, could only tell women what to avoid, not what to buy.

Despite the mixed reaction from the breast cancer and consumer activist community, the NCI was determined to proceed with the trial, and by 1992, NCI was forging ahead with plans for a trial.

THE BREAST CANCER PREVENTION TRIAL: FROM CONTROVERSY TO SCANDAL AN "HISTORIC SUCCESS"

When the activists realized they were not going to be able to stop the research, they shifted their efforts to limiting the eligibility criteria for trial enrollment. If successful, this effort could have ensured that the healthy women who would be given tamoxifen would at least be those who were at a high enough risk of developing breast cancer to counterbalance the other health risks to which they would be exposing themselves.

"We believe the definition of 'high-risk' women used in this protocol is appallingly broad," asserted 26 leading researchers in a November 1991 letter to the Food and Drug Administration (FDA) about the tamoxifen trial. "While a small trial of extremely high-risk women may be defensible, a large trial that includes numerous healthy women is premature and unethical." The letter urged the agency to ask investigators "to more clearly define and justify the level of risk that makes a woman eligible." NCI continued to ignore most of the concerns raised, arguing that limiting eligibility would make it too difficult to find women to participate in the trial.

Consumer activists did have some success, however, in persuading the FDA to include complete risk information in the informed consent form that trial subjects were to be given prior to agreeing to participate. The approved form included information about the known risks of the drug and also about what was unknown about it.

Unfortunately, only a few months into the trial, a Congressional investigation, launched at the suggestion of skeptical activists by the Human Resources and Intergovernmental Subcommittee of the House of Representatives Government Operations Committee, discovered that nearly two-thirds of the consent forms being used in the trial omitted one or more of the six key points in the model consent form that had been approved by the FDA.

"The NIH and the principal investigator in the study had given out a model consent form but hadn't bothered to check if the informed consent forms being used were at all similar," explains Diana Zuckerman, who worked as staff on the Congressional investigation. "As a result, many were inadequate or had left out crucial information about risk."

Some of the consent forms in use were so weak as to be meaningless, offering women only general statements about the hope that the research would save lives and providing no concrete information about the risks to which participants were exposing themselves.

The Congressional committee staff found that neither the NIH nor the principal investigator had copies of the forms that were being used. "They had never asked for them or seen them," recalls Zuckerman, who now directs the National Center for Policy Research for Women and Families in Washington, D.C. After this investigation, the NIH tightened its informed consent standards, improving the process not just for the tamoxifen trial but for future research as well.

Two years into the trial, researchers ran into another hitch. In January 1994, NCI began to warn investigators that tamoxifen can cause fatal endometrial cancer. This risk had been downplayed and dismissed in the informed consent forms with the claim that endometrial cancer can be caught early and cured, though research results published in April 1994 indicated that officials had been aware of endometrial cancer deaths in women taking tamoxifen before the prevention trial began.

Critics of the trial were outraged: not only were women being exposed to unknown risks without adequate warning, but even the information about the known risks was being withheld from them. Scientists were concerned as well. Dr. Richard Love, a leading tamoxifen researcher, told the New York Times, "The trial should be stopped."

In the midst of this discovery, a major research scandal hit the NCI. A leading researcher was found to have submitted falsified data in another breast cancer trial.

At a Congressional hearing about the falsified data, both Dr. Samuel Broder, the NCI's director, and Zeneca's International Medical Director John Patterson testified about the tamoxifen-induced endometrial cancer deaths. (Zeneca merged earlier this year with the Swedish pharmaceutical company Astra to form AstraZeneca, the third largest pharmaceutical company in the world in terms of sales.)

Patterson denied that Zeneca was responsible for the delay in informing trial participants about the endometrial cancer deaths and sought to distance Zeneca from the trial. After acknowledging that the "deaths have brought into question the wisdom of continuing the tamoxifen prevention trial," he emphasized that "Zeneca is not sponsoring or endorsing the tamoxifen breast cancer prevention trial."

In his testimony, Broder simply reported that two of the institute's advisory boards had recommended that the breast cancer prevention trial should go on and proceeded to discuss planned changes to strengthen record keeping and reporting procedures.

Activists called for the Public Health Service (PHS) to create a blue ribbon commission to reassess the design and conduct of the tamoxifen prevention trial, but once again NCI prevailed, persuading the PHS to allow the trial to continue.

Still, the negative publicity about the deaths and the scandal had had an impact. In spite of the researchers, it seemed, women were getting the message about the cancer-causing risks of tamoxifen. Fewer and fewer women were willing to enroll in the trial. In the end, it was mainly women at the very most extreme levels of risk who would even consider going into the trial. For those women, just as the activists had said from the beginning, the risk-benefit ratio of taking tamoxifen balanced out. In September 1996, the NCI announced that it was stopping enrollment of the women in the trial at 13,000 instead of the original goal of 16,000.

The initial results of the breast cancer prevention trial were released in 1998, showing a 45 percent reduction in breast cancer among the high-risk participants who took tamoxifen. NCI hailed the results as "remarkable" and an "historic success."

Activists, however, continued to raise concerns about the risks of the drug. They criticized the idea that women should be willing to trade one disease for another, pointing out that while there were 69 fewer cases of invasive breast cancer in the group who took tamoxifen, there were also an additional 19 cases of endometrial cancer and 29 cases of serious blood clots and stroke.

As Breast Cancer Action pointed out in a press statement issued following the release of the results, the original question about the trial still remained: "Why is it that when we demand prevention, the government responds by testing a pill Ñ and a known carcinogen at that Ñ instead of focusing on what is causing the increased incidence of breast cancer?"

Breast cancer activists also pointed out that the trial findings were only initial results and that the long-term effectiveness of tamoxifen for prevention remained unknown. Since the benefits of many other drugs given to mid-life and older women decrease over time, the groups asked whether this would also be true for tamoxifen. If that is the case, the groups noted, there was no reason to believe that over time the benefits of the drug would continue to outweigh the risks.

APPROVAL FOR RISK REDUCTION: SELLING FEAR

Soon after the trial results were released, Zeneca applied to the FDA for approval to market Nolvadex for breast cancer prevention. Although the FDA approved the application in October 1998, it did respond to activists' criticisms of the research by limiting the approved indication to risk reduction for women at high risk of breast cancer rather than general breast cancer prevention. Though this may seem like a semantic difference, activists hoped that it would limit the company's target market for the drug and help ensure that the drug would be used primarily by women whose level of risk for breast cancer warrants it.

Zeneca representatives privately told activists that the company did not want millions of healthy women to start using tamoxifen as soon as the drug was approved, but the company's public statements and marketing soon showed that it was going to cast as wide a net as possible in order to sell as much drug as possible. Under the FDA's newly relaxed regulations for ads targeting consumers (see "Peddling Pills," Multinational Monitor, January/February 1999), Zeneca had great leeway to promote the drug as it wanted. The company quickly launched a direct-to-consumer advertising campaign, telling women that taking Nolvadex could reduce their risk of getting breast cancer and urging women to ask their doctors to give them a breast cancer risk assessment test.

In the first six months after approval of Nolvadex, Zeneca used three different ads for consumers, all of which have received significant criticism. The first was a magazine ad which, although only nine words long, implied that the drug was effective for a broader range of women than the trial results supported. After the National Women's Health Network wrote a letter to the FDA alerting it to the problem, the agency required the company to pull the ad.

That was followed by the television ad with the collage of women's images and voices. In order to avoid even the limited FDA regulations that still apply to broadcast advertisements, Zeneca took advantage of the fact that it has the only drug approved for reducing the risk of breast cancer and ran what is known in the industry as a "help-seeking" ad. (Help-seeking advertisements do not mention a product by name, but simply describe a health problem and encourage viewers to talk to a doctor about what their options may be; companies typically use help-seeking ads when they know that they control enough of the market that the vast majority of consumers who ask doctors about their options for treatment of a specific health problem will end up with prescriptions for the company's product.)

Breast cancer activists assert that Zeneca's help-seeking ad inappropriately seeks to exploit women's fear of breast cancer to sell Nolvadex. Brenner, of Breast Cancer Action, acknowledges that "the ad is saying some of the very same things we say, but then it tells women that what they should do is call a phone number to get information from a company that wants to sell them a drug." The difference, Brenner explains, "is the punch line. When we put out that information, we're trying to get women involved on a political level in the effort to eradicate breast cancer. The Zeneca ad suggests that what women should do is take a pill."

The ad sends the message that every woman Ñ no matter what her age, family history or health status Ñ is at risk for breast cancer, and it includes the standard Nolvadex product tag line, "There is something you can do." The implied message is that there is something every woman can do to avoid getting breast cancer (take Nolvadex). But since the ad is not promoting a specific product, the FDA cannot require the company to change the ad or include any balancing information about the fact that Nolvadex has only been shown to be effective for women at very high risk for breast cancer.

Health advocates fear the ads will stimulate women's anxiety about breast cancer, and lead them to press their physicians to prescribe Nolvadex inappropriately.

The problem, health advocates believe, is compounded by flaws in the breast cancer risk assessment test which clinicians use to identify women in the high risk category (defined by the same terms used for the trial).

"The women who actually took part in the trial were at much higher risk for breast cancer than the group that is defined by the eligibility criteria, and the risk assessment tool is based on the eligibility criteria," explains Maryann Napoli, associate director of the New York City-based Center for Medical Consumers. "This means that the results of the trial may not hold true for all women that the tool defines to be at high risk." In other words, trial participants were at a very high risk for breast cancer, so the proof of effectiveness may not apply to women at lower risk who also fit the eligibility criteria.

Activists also point out that the test is based on data from white women who get breast cancer more often than women of any other race or ethnicity, so the test will overestimate risk for women of color.

Additionally, Napoli says, "There are some important omissions in the risk assessment tool. It doesn't provide an assessment of a woman's risk for developing endometrial cancer, blood clots or stroke which are possible adverse effects of taking tamoxifen." This limitation means that the test does not help potential users to weigh their risk of breast cancer against the possible negative effects of the drug.

PROFIT OVER TRUE PREVENTION

From the earliest inception of the idea that tamoxifen could be used for breast cancer prevention to the implementation of the Nolvadex advertising campaign, the tamoxifen experience has demonstrated the tension within the health field between profit-driven decision-making and consumer interests. At every stage when there were decisions to be made about what to research, the design of the trial, whether to end the trial early, the analysis of the results and the campaign to make women aware of the new drug option, there has been a struggle between those who wanted to ensure that women were not exposed to unnecessary health risks without being given the chance to make an informed decision based on complete and accurate information and those who wanted to move forward quickly toward the day when there would be a breast cancer prevention product to sell to women.

With these conflicting motivations at work, win-win situations are very difficult to achieve. And until a profit potential is discovered in true prevention options, patient and consumer activists seeking ways to prevent breast cancer and other serious illnesses are likely to be on the losing end of the research and marketing decisions.

Amy Allina is program director and Cindy Pearson is executive director of the National Women's Health Network. The Network was among the earliest U.S. advocates for breast cancer prevention research and was one of the first to raise safety questions about the use of tamoxifen by healthy women. To receive more information about tamoxifen, contact the Network to request a Tamoxifen for Healthy Women information packet.